Computational Modeling of Hepatic Lipid and Lipoprotein Metabolism

NCSB / NBIC Modelers-Bioinformatics Meeting

26-02-2010

Overall aim:

Development of mathematical models describing lipid and carbohydrate metabolism at whole body and organ specific level in mice

Leiden University Medical Center BioModeling & bioInformatics Biomedical NMR

triglyceridecholesterol ester

VLDL

IDLLDL

FFA

HDL

chylomicronremnants

Véniant et al.

TGTG

Liang et al.Zhang et al.Boogaerts et al.

TG

TG

Grefhorst et al.Davis et al.Dixon et al.

TG

Millar et al.Wong et al.Horton et al.

FA metabolism

Lipogenesis

Lipolysis

Ketogenesis

apoB metabolism

Remnant catabolism

NEFA

Part I Part II

GPAT / AGPAT

G3P

LPA

PA

DAG

FA

Glycerol

DGAT1

TG

PPAP2

FA

FA FA

GPAT / AGPAT

MG

TGH

HSL:FABP4

HSL:FABP4

FA

MGL

FA

GK

HSL:FABP4

C

CE

FAFA

ACAT

TG CE

Apo B

Apo B

FFA

FAFA

TG / CE / Glycerol

MTP

DGAT2

FAFAS

MGK

G3P

DGK

MGAT

Liver

Peripheral

Lipoprotein Type Matrix

GPAT / AGPAT

G3P

LPA

PA

DAG

FA

Glycerol

DGAT1

TG

PPAP2

FA

FA FA

GPAT / AGPAT

MG

TGH

HSL:FABP4

HSL:FABP4

FA

MGL

FA

GK

HSL:FABP4

C

CE

FAFA

ACAT

TG CE

Apo B

Apo B

FFA

FAFA

TG / CE / Glycerol

MTP

DGAT2

FAFAS

MGK

G3P

DGK

MGAT

Liver

Peripheral

Lipoprotein Type Matrix

, , , ,

, , , , , , , ,

[ ][ ] [ ] [ ] [ ][ ]

[ ][ ] [ ] [ ] [ ]DAG MG MG GLC MG LPA MG DAG

m DAG MG m MG GLC m MG LPA m MG DAG

V MG FA V MG V MG V MGd MG

dt K MG FA K MG K MG K MG

, , ,

, , , , , ,

[ ] [ ][ ] [ ][ ]

[ ] [ ][ ] [ ]C C CE CE C

Cm C m C CE m CE C

V C V C FA V CEd CV

dt K C K C FA K CE

GPAT / AGPAT

G3P

LPA

PA

DAG

FA

Glycerol

DGAT1

TG

PPAP2

FA

FA FA

GPAT / AGPAT

MG

TGH

HSL:FABP4

HSL:FABP4

FA

MGL

FA

GK

HSL:FABP4

C

CE

FAFA

ACAT

TG CE

Apo B

Apo B

FFA

FAFA

TG / CE / Glycerol

MTP

DGAT2

FAFAS

MGK

G3P

DGK

MGAT

Liver

Peripheral

Lipoprotein Type Matrix

, , , ,

, , , , , , , ,

[ ][ ] [ ] [ ] [ ][ ]

[ ][ ] [ ] [ ] [ ]DAG MG MG GLC MG LPA MG DAG

m DAG MG m MG GLC m MG LPA m MG DAG

V MG FA V MG V MG V MGd MG

dt K MG FA K MG K MG K MG

, , ,

, , , , , ,

[ ] [ ][ ] [ ][ ]

[ ] [ ][ ] [ ]C C CE CE C

Cm C m C CE m CE C

V C V C FA V CEd CV

dt K C K C FA K CE

LiteratureQuantitative data generation

Bijland et al.

Exhaustingly searching for

kinetic parameters and specie

concentrations

parameter estimation

• Text mining techniques to infer quantitative information (PHASAR / BioMeta)

• Inferring pathway topologies in a more structured way

GPAT / AGPAT

G3P

LPA

PA

DAG

FA

Glycerol

DGAT1

TG

PPAP2

FA

FA FA

GPAT / AGPAT

MG

TGH

HSL:FABP4

HSL:FABP4

FA

MGL

FA

GK

HSL:FABP4

C

CE

FAFA

ACAT

TG CE

Apo B

Apo B

FFA

FAFA

TG / CE / Glycerol

MTP

DGAT2

FAFAS

MGK

G3P

DGK

MGAT

Liver

Peripheral

Lipoprotein Type Matrix

cholesterol

trig

lyce

ride

0 1000 2000

0

500

0

100

00

Cholesterol: 1000Triglyceride: 5000

particle uptake

hydrolysis

Different lipoprotein types− Based on triglyceride and cholesterol content− Color represents concentration of lipoprotein type

content transfer

VLDL production

cholesterol

trig

lyce

ride

• VLDL production

• Particle uptake

• Hydrolysis

• CETP

910

• Apo B

• TG• CE

cholesterol

trig

lyce

ride

• VLDL production

• Particle uptake

• Hydrolysis

• CETP

109

cholesterol

trig

lyce

ride

109

1

• VLDL production

• Particle uptake

• Hydrolysis

• CETP

cholesterol

trig

lyce

ride

10 10

1

9 9

1

• VLDL production

• Particle uptake

• Hydrolysis

• CETP

CETP

Acknowledgements

Peter Hilbers Natal van Riel Jeroen Jeneson Joep VanlierJoep SchmitzÇeylan Cölmekçi

Ko Willems van DijkJan Bert van Klinken Sjoerd van den Berg Silvia Bijland